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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1200.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

JAM-C Induces Endothelial Cell Permeability Through Its Association and Regulation of β₃ Integrins

Xiaochun Li; Milena Stankovic; Boris P.-L. Lee; Michel Aurrand-Lions; Chris N. Hahn; Ying Lu; Beat A. Imhof; Mathew A. Vadas; Jennifer R. Gamble

From the Division of Human Immunology (X.L., M.S., C.N.H.), Hanson Institute, SA Pathology, Adelaide, Australia; the Department of Pathology (B.P.-L.L., B.A.I.), University of Geneva, Switzerland; UMR891 (M.A.-L.), INSERM, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, France; and the Centenary Institute of Cancer Medicine and Cell Biology, Department of Medicine (Y.L., M.V., J.G.), Sydney NSW, Australia; Medical Foundation (J.R.G.), University of Sydney NSW, Australia.

Correspondence to Jennifer Gamble, Centenary Institute of Cancer Medicine and Cell Biology, Locked bag#6, Newtown, NSW, Australia. E-mail j.gamble{at}centenary.org.au

Objectives— The molecular mechanisms regulating vascular permeability are only now being elucidated. The junctional adhesion molecule (JAM) JAM-C has been linked to the induction of vascular permeability. We sought to understand the mechanism whereby JAM-C may disrupt junctional integrity in endothelial cells (ECs).

Methods and Results— We show here that JAM-C alters permeability through modulation of integrin activity. JAM-C overexpression results in an increase in JAM-C at junctions and an increase in permeability. Conversely, knockdown of JAM-C by siRNA results in a reduction in permeability. JAM-C associates with vβ3 integrin and regulates its localization and activity. JAM-C also inhibits the activation state of the β₁ integrin although it does not associate with this integrin. These changes induced on the integrins are mediated through regulation of the small GTPase, Rap1b but not Rap1a. Thrombin, a powerful inductor of vascular leak, causes localization of JAM-C into the junctions, whereas angiopoietin-1, an inhibitor of permeability, prevents JAM-C translocation.

Conclusions— The regulation of EC junctional integrity involves the coordinated and dynamic modification of localization and activity of junctional stabilizers such as the integrin β₃ and the destabilizer, JAM-C.

Key Words: junctional adhesion molecule C • endothelial permeability • integrin • Rap1b • VE cadherin